The objective of this pilot subproject is to propose and test a novel major mechanism by which activities of the serotonergic dorsal raphe (DRN) neurons are regulated. This study has potential clinical relevance as DRN 5-HT neurons are purported to play a central role in the pathophysiology of major depression, anxiety and other disorders. The most widely accepted theory now hypopthesizes autocoid effects of 5-HT on its somatodendritic autoreceptors. We hypothesize that an additional or altemative major site of regulation is at the axo-axonic synapse between a feedback pathway from the DRN to the GABAergic afferents that project from forebrain and hypothalamic sources to the lateral habenula nucleus (LHb). This DRN-LHb projection would be part of a feedback loop because the LHb is the major source of direct afferent input to the DRN. We further hypothesize that this synaptic junction is a major drug target of selective serotonin reuptake inhibitors (SSRI's). Our specificaims are: 1) to determine whether the afferent synaptic input to the LHb via the stria medullaris is modulated by a 5-HT input from the DRN in a manner consistent with negative feedback from the DRN; 2) to determine whether SSRI's exert acute and/or long-term effects on this proposed serotonergic feedback on stria-medullarise voked responses; 3) to build a technical base for future in-depth investigation of the cellular electrophysioloical mechanism of the feedback. We will use conventional intracellular recording coupled with electrical stimulation of afferent pathways to test for modulatory actions of the presumed feedback on the afferent input to the LHb. The feedback pathway will be activated by stimulation of the fasciculus retroflexus just before or during stimulation of the stria medullads. If we can demonstrate occurrence of the feedback, we will characterize this feedback. Broad spectrum 5-HT antagonists will be used to test its serotonergicnature. The 5-HT subtypes will be identified by means of subtype-specific antagonists. Dose-response studies will be performed to quantify the potency of feedback modulation. We also propose 2 variations to this feedback loop model, and neuropharmacological tests to distinguishthe merits of each model. The effect of bath-application or a 2-week injection of SSRI's on this feedback modulationis studied. A reductionin the modulation would support this junction as a major SSRI therapeutic target.